Abstract 954: <i>PIK3CA</i> mutation induces immunogenicity and increases the immune checkpoint inhibitor response in urothelial carcinoma
Authors: Harvey Yu-Li Su, Ling-Yi Xiao, Shih-Yu Huang, Li-Chung Chang, Yi-Hua Chen, Hao-Lun Luo, Chia-Ling Wu
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint inhibitor (ICI) has been widely used for advanced urothelial carcinoma (mUC) globally. However, little is known about the potential predictive factors of the ICI response. The study aims to identify a potential biomarker to predict ICI response in UC. Material and methods: We performed targeted next generation sequencing (NGS) of pre-treatment tumor Formalin-fixed paraffin-embedded (FFPE) samples by using ACTOnco® comprehensive genomic panel (ACT Genomics, Co. Ltd., Taiwan) to target all coding exons of 440 cancer-associated genes. We retrospective analyzed a total of 70 patients with mUC underwent at least one cycle of ICI with or without chemotherapy at Kaohsiung Chang Gung Memorial Hospital between April 2016 and November 2019. Patients were defined as responders (CR/PR) and non-responders (SD/PD) according to the RECIST evaluation. TMB was estimated by calculating all coding exons variants, including somatic non-synonymous, frameshift and splice site variants. Results: A total of 55 UC tumor samples passed QC process were analyzed. The median age was 67, and 74% of all patients were in ICI monotherapy cohort. The most common genetic alterations were TP53 (66%), KMT2D (42%) and MUC16 (32%). In ICI monotherapy group, responders had a higher TMB than non-responders (median 19.5 vs 6.5 mt/Mb; p = 0.004). Patients with high TMB on ICI monotherapy had a significantly longer PFS (14.6 vs 2.9 months; p = 0.003) and OS (NR vs 11.0 months; p = 0.01) than TMB low patients. We found that PIK3CA (32% vs 3%), UBR5 (23% vs 0%), PRKDC (32% vs 10%) were the top 3 enriched mutations between responders and non-responders. All PIK3CA mutation were hot-spot mutation, and tumor harbored PIK3CA mutation had a median high TMB than PIK3CA wild type in UC, NSCLC, breast and colorectal cancer. By analyzing tumor and immune microenvironment by TISIDB platform, UC with PIK3CA mutation was highly associated with increasing MHC molecules expression (HLA-A, HLA-B, HLA-C, B2M) in UC and gastric cancer. In vitro study, we confirmed anti-PDL1 with PBMC had a synergistic cytotoxicity in PIK3CA mutated cell lines (BFTC-909, AGS and DLD-1), but not in PIK3CA wild type cell lines (T24, RT4, UMUC-14, N87 and SW837). Knocking-down PIK3CA expression diminished the cytotoxic activity of anti-PDL1 with PBMC in BFTC-909 and AGS cells. PIK3CA down-regulation inhibits antigen presentation machinery process. We confirmed that knockout PIK3CA gene function by CRISPR/Cas9 decreased MHC1 and B2M molecules expression, and showing modest resistance to ICI than mice with preserved PIK3CA function. Conclusion: UC with PIK3CA missense mutation exhibits a higher immunogenicity through enhancing MHC class I and B2M expression. PIK3CA missense mutation is a potential predictive marker for ICI response in UC. Citation Format: Harvey Yu-Li Su, Ling-Yi Xiao, Shih-Yu Huang, Li-Chung Chang, Yi-Hua Chen, Hao-Lun Luo, Chia-Ling Wu. PIK3CA mutation induces immunogenicity and increases the immune checkpoint inhibitor response in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 954.